The present invention relates to the encapsulation of hydrophobic molecules within polymeric micelles, and, in particular, to the encapsulation of materials such as biologically or pharmaceutically active hydrophobic molecules. The present invention further relates to pharmaceutical dosage forms comprised of thermodynamically stable aqueous solutions, suspensions or dispersions of the polymeric micelle encapsulated, biologically or pharmaceutically active, hydrophobic molecules. The present invention also relates to treatment methods employing the pharmaceutical dosage forms of the present invention.
The efficacy of pharmaceuticals is strongly affected by the way they are administered. There are many problems associated with the introduction of free drugs into the bloodstream. first, many drugs are deactivated when delivered in the free form. Although deactivation mechanisms can be quite complicated, interactions between drugs and components in the bloodstream (e.g., proteins and enzymes, as well as water) are the most common factors. Second, free drugs frequently have short circulation times (i.e., minutes) and are quickly excreted from the body. Third, free drugs are often distributed randomly among organs and tissues. The inability of most drugs to discriminate between normal and diseased cells contributes to drug toxicity, especially for anti-tumor drugs.
Another problem associated with drug delivery is water solubility; most drugs are too hydrophobic to be water-soluble. This water-insolubility limits both the applicable administration methods as well as dosage levels. Over the years, drug delivery system have been devised to overcome all or some of the problems described above, such as enhancing solubility and efficacy, prolonging circulation time, achieving controlled release, and providing site-specific delivery. Delivery systems range from the use of starch as an additive to form tablets, to the use of capsules to achieve slow release, to more complex devices consisting of hydrogels, polymers, liposomes and various surfactants.
The use of surfactants is one of the promising answers for drug delivery. The use of polymeric surfactants as drug delivery devices has been reviewed extensively, and several successful examples have been demonstrated. For example, micelles have a hydrophobic core that can solubilize hydrophobic materials, such as drugs, as well as a hydrophilic outer shell that makes the assembly water-soluble. Polymeric surfactants have been favored over smaller organic surfactants because they usually have much lower critical micelle concentrations, or cmc""s (about 10xe2x88x925 M), compared to smaller organic surfactants (about 10xe2x88x922 M). Site-specific drug delivery has been shown possible by controlling the size or the surface properties of the polymeric surfactants. However, the thermodynamic instability that is both concentration and temperature dependent of these conventional micelles limits their use in drug delivery. The reversal of micelle to surfactant causes a flux of drug concentration which can cause serious toxicity problems.
One way to overcome the thermodynamic instability of conventional micelles is to construct an assembly that topologically resembles the micelle architecture but with all components covalently bound together. These assemblies are polymers consisting of both hydrophobic (usually aliphatic) and hydrophilic (ionic or non-ionic) components. Most examples of such materials are dendrimers with hydrophilic end functional groups based on amine or carboxylate groups. In a few systems, guest molecules have been entrapped within the structures. Jansen et al., JACS, 117, 4417-4418 (1995) demonstrated that different entrapped guest molecules could be liberated by selective chemical removal of the outer shell components. In general, unimolecular micelles showed either dynamic encapsulation (See, Newkome, et al., Angew. Chem. Int. Ed. Engl., 30, 1178-1180 (1991)) or physical entrapment (Jansen et al.) of guest molecules depending on the steric compactness of the structures. The guest molecules either escape from the unimolecular micelles too soon (in the case of dynamic encapsulation) or do not diffuse at all (in the case of physical entrapment) unless the micellar structures are physically disrupted.
Liu et al., Polym. Preprint., 38(2), 582-583 (1997) report the synthesis of hyper-branched polymeric micelles for encapsulation of small hydrophobic organic molecules. There remains a need for suitable delivery systems for the administration of hydrophobic drugs.
This need is met by the present invention. The present invention provides new polymeric micelles that are useful for solubilizing a variety of hydrophobic materials in water, particularly hydrophobic materials with biological or pharmaceutic activity, which greatly simplifies the preparation of aqueous dosage forms of biologically or pharmaceutically active hydrophobic materials.
Therefore, according to one aspect of the present invention, a polymer is provided having a structure selected from:
R(xe2x80x94Oxe2x80x94R1,)x and R(xe2x80x94NHxe2x80x94R1)x
wherein R(xe2x80x94Oxe2x80x94)x is a polyol moiety and R(xe2x80x94NHxe2x80x94)x is a polyamine moiety, with x being between 2 and 10, inclusive, and each R1 independently has the structure: 
wherein 
is a divalent amino acid moiety with R2 being a covalent bond or having from 1 to 8 carbon atoms, and y and z are between 0 and 10, inclusive, provided that y and z are not both 0; 
is a divalent dicarboxylic acid moiety in which R3 is an alkylene or cycloalkylene group containing from 1 to about 15 carbon atoms substituted with a total of from 1 to about 10 hydroxyl groups, with at least a portion of the hydroxyl groups being acylated with 3 to 24 carbon atom carboxylic acids; and
R4 is a poly(alkylene oxide) having the structure:
R5xe2x80x94(xe2x80x94R6xe2x80x94Oxe2x80x94)axe2x80x94R6xe2x80x94Qxe2x80x94
with R5 selected from 1 to 40 carbon atom alkyl groups, xe2x80x94Oxe2x80x94, OR7xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NHR7, NR7R8, xe2x80x94Cxe2x80x94OH, xe2x80x94Cxe2x80x94OR7, xe2x80x94Cxe2x80x94Oxe2x80x94Cxe2x80x94R7, xe2x80x94Cxe2x80x94NH2, Cxe2x80x94NHR7, and xe2x80x94Cxe2x80x94NR7R8; R6, R7 and R8 are independently selected from 2 to 40 carbon atom, straight chain or branched alkylene groups; Q is a divalent linkage moiety; and a is between 2 and 110, inclusive;
provided that when y is zero and R is a 1,1,1-tris(hydroxyphenyl)ethane moiety, the divalent dicarboxylic moiety is not an acylated mucic acid moiety.
The polymers of the present invention encapsulate a wide variety of hydrophobic molecules. The encapsulation is a physical encapsulation, and not a simple association of the hydrophobic molecule with the polymer. According to a preferred embodiment of the present invention, upon formation of the encapsulated hydrophobic molecule, the polymer is recovered and rinsed to remove any residue of non-encapsulated hydrophobic molecules.
Therefore, according to another aspect of the present invention, a hydrophobic molecule encapsulated in a polymer is provided, wherein the polymer has a structure selected from:
R(xe2x80x94Oxe2x80x94R1,)x and R(xe2x80x94NHxe2x80x94R1)x
wherein R(xe2x80x94Oxe2x80x94)x is a polyol moiety and R(xe2x80x94NHxe2x80x94)x is a polyamine moiety, with x being between 2 and 10, inclusive, and each R1 independently has the structure: 
wherein 
is a divalent amino acid moiety with R2 being a covalent bond or having from 1 to 8 carbon atoms, and y and z are between 0 and 10, inclusive, provided that y and z are not both 0; 
is a divalent dicarboxylic acid moiety in which R3 is an alkylene or cycloalkylene group containing from 1 to about 15 carbon atoms substituted with a total of from 1 to about 10 hydroxyl groups, with at least a portion of the hydroxyl groups being acylated with 3 to 24 carbon atom carboxylic acids; and
R4 is a poly(alkylene oxide) having the structure:
R5xe2x80x94(xe2x80x94R6xe2x80x94Oxe2x80x94)axe2x80x94R6xe2x80x94Qxe2x80x94
with R5 selected from 1 to 40 carbon atom alkyl groups, xe2x80x94Oxe2x80x94, xe2x80x94OR7, xe2x80x94NHxe2x80x94, xe2x80x94NHR7, xe2x80x94NR7xe2x80x94R8xe2x80x94Cxe2x80x94OH, xe2x80x94Cxe2x80x94OR7, xe2x80x94Cxe2x80x94Oxe2x80x94Cxe2x80x94R7, xe2x80x94Cxe2x80x94NH2, xe2x80x94Cxe2x80x94NHR7 and xe2x80x94Cxe2x80x94NR7R8; R6, R7 and R8 are independently selected from 2 to 40 carbon atom, straight chain or branched alkylene groups; Q is a divalent linkage moiety; and a is between 2 and 110, inclusive;
provided that when y is zero and R is a 1,1,1-tris(hydroxyphenyl)ethane moiety, the divalent dicarboxylic acid moiety is not a mucic acid moiety acylated with carboxylic acids having less than six carbon atoms.
The present invention incorporates the discovery that acylation with carboxylic acids of six carbon atoms or greater produces an unexpected increase in the affinity of the polymer interior for hydrophobic molecules. The polymers of the present invention meet the need for unimolecular micellar encapsulants for hydrophobic molecules having biological or pharmaceutical activity that are thermodynamically stable in aqueous media. Accordingly, the hydrophobic molecules encapsulated by the polymers of the present invention are preferably hydrophobic molecules with biological or pharmaceutical activity.
Furthermore, because the polymer encapsulates of the present invention are thermodynamically stable in aqueous media, the present invention also includes aqueous solutions, suspensions and dispersions of polymer encapsulated hydrophobic molecules. Again, the hydrophobic molecules are preferably have biological or pharmaceutical activity.
The polymers of the present invention are ideal vehicles for the delivery of hydrophobic molecules with biological or pharmaceutical activity to patients in need thereof. Accordingly, the present invention also includes pharmaceutical dosage forms containing the polymers of the present invention encapsulating hydrophobic molecules having biological or pharmaceutical activity, and a pharmaceutically acceptable carrier. In addition, the present invention includes methods of treating a patient in need thereof with a hydrophobic molecule having biological or pharmaceutical activity by administering to the patient an effective amount of a pharmaceutical dosage form of the present invention.
While the pharmaceutical dosage forms may be aqueous solutions, suspensions or dispersions, other types of compositions are included among the dosage forms of the present invention, as well as among the dosage forms that are administered by the treatment methods of the present invention. The polymer encapsulated hydrophobic molecules may be administered in a solid form by way a of a tablet or capsule, for example, to be dissolved in the digestive tract, and, consequently, in the bloodstream.
Alternatively, pharmaceutical dosage form compositions may be prepared for topical administration. The present invention incorporates the discovery that the encapsulation of hydrophobic molecules by the polymers of the present invention enhances transdermal delivery of molecule. Absorption through the skin can be increased by a factor of up to 1000. Thus, the pharmaceutical dosage forms of present invention include dosage forms suitable for transdermal delivery, which, in addition to aqueous solutions, suspensions or dispersions, also include aqueous gels and water-in-oil and oil-in-water emulsions. The dosage form may be applied directly to the skin as a lotion, cream or salve, or a transdermal drug delivery device such as a transdernal patch may be employed, in which the polymer encapsulated hydrophobic molecule is retained in the active agent reservoir of the patch.
The polymer encapsulated hydrophobic molecules may be the only pharmaceutically or biologically active material in the topical dosage form, or the dosage form may contain the hydrophobic molecules stabilized in the pharmaceutical carrier by other means, so that the polymer encapsulated hydrophobic molecule provides a xe2x80x9cburst effectxe2x80x9d initial dose, followed by a sustained delivery of the non-encapsulated molecule.
Therefore, according to another aspect of the present application, a method for transdermal delivery to a patient in need thereof of a hydrophobic molecule having biological or pharmaceutical activity is provided. An effective amount of a topical dosage form containing the hydrophobic molecule encapsulated by the polymer of the present invention and a pharmaceutically acceptable topical carrier, is applied to the skin or mucosa of the patient.
Preferred polymers according the present invention hydrolyze into components known to be biocompatible, i.e., sugars, fatty acids, amino acids and poly(ethylene glycol). This also results in low cytotoxicity of the polymer and its hydrolysis products. The poly(alkylene oxide) units enhance the immunogenicity of the encapsulate, enabling the hydrophobic molecules to evade the body""s immune system, thereby increasing the circulation time of the hydrophobic molecule. This allows for effective treatment with reduced quantities of the hydrophobic molecule, which, together with the enhanced immunogenicity, prevents or reduces the severity of incidents of toxic side effects.